Preservation of the body cell mass is a major goal of nutritional therapy. Methods for assuring this preservation have primarily depended on the mass action of hyperalimentation, either oral or parenterally. The object of this investigation is to attempt systematically to develop a metabolic rationale for optimal substrate infusates during periods of starvation. Recognizing the importance of adequate fat mobilization and the favorable effect of starvation ketosis during periods of negative caloric balance, we have undertaken to determine the protein sparing effect of amino acid infusates free of glucose. In this state mobilization of endogenous fat stores must be of primary concern. This important fact has previously received very little consideration. We have developed a rationale which recognizes that the anabolic effect of insulin on protein metabolism is desirable, but the anabolic effect of insulin on lipid metabolism is potentially harmful during starvation. Due to the relative sensitivity of muscle and adipose tissue to insulin, it is possible to exert an anabolic effect on muscle protein synthesis while reducing the risk of insulin interfering with fat mobilization. However, during the acute phase of injury the stress response including cathecholamines and glucocorticoids are so effective in meeting the metabolic demands, no benefit is possible from the exogenous infusate of amino acid, carbohydrate or fat when compared with total starvation and injury. In sepsis, the beneficial effect of cathecholamines is blocked allowing hyperinsulism and lowered free fatty acid levels. Thus increased lipolysis occurs. It is possible that special containing branched chain amino acids on their analogues may palliate this pathological state.